Inhibition of SRC family kinases facilitates anti-CTLA4 immunotherapy in head and neck squamous cell carcinoma
The immune system plays a critical role in the establishment, development, and progression of head and neck squamous cell carcinoma (HNSCC). As treatment with single-immune checkpoint agent results in a lower response rate in patients, it is important to investigate new strategies to maintain favorable anti-tumor immune response. Herein, the combination immunotherapeutic value of CTLA4 blockade and SFKs inhibition was assessed in transgenic HNSCC mouse model. Our present work showed that tumor growth was not entirely controlled when HNSCC model mice were administered anti-CTLA4 chemotherapeutic treatment. Moreover, it was observed that Src family kinases (SFKs) were hyper-activated and lack of anti-tumor immune responses following anti-CTLA4 chemotherapeutic treatment. We hypothesized that activation of SFKs is a mechanism of anti-CTLA4 immunotherapy resistance. We, therefore, carried out combined drug therapy using anti-CTLA4 mAbs and an SFKs’ inhibitor, dasatinib. As expected, dasatinib and anti-CTLA4 synergistically inhibited tumor growth in Tgfbr1/Pten 2cKO mice. Furthermore, dasatinib and anti-CTLA4 combined to reduce the number of myeloid-derived suppressor cells and Tregs, increasing the CD8+ T cell-to-Tregs ratio. We also found that combining dasatinib with anti-CTLA4 therapy significantly attenuated the expression of p-STAT3Y705 and Ki67 in tumoral environment. These results suggest that combination therapy with SFKs inhibitors may be a useful therapeutic approach to increase the efficacy of anti-CTLA4 immunotherapy in HNSCC.
KeywordsCTLA4 Dasatinib MDSCs Tregs Immunotherapy HNSCC
Cytotoxic T-lymphocyte-associated antigen 4
Head and neck squamous cell carcinoma
Myeloid-derived suppressor cells
Src family kinases
Tumor infiltrate lymphocytes
We thank Zhi-Yong Chen and Dong Chen for excellent technical support. And also thank Wuhan Institute of Biotechnology for their Public Technology Service Platform. Meanwhile, this study was supported by National Natural Science Foundation of China (NFSC): 81672668, 81472528, and 81472529, and the Fundamental Research Funds for the Central Universities (2042017kf0171).
Compliance with ethical standards
Animal studies were approved and supervised by the Animal Care and Use Committee of Wuhan University. The ethical approval number is 2014C66.
Conflict of interest
The authors declare that they have no competing interests.
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